A wide variety of substituted guanidines are disclosed in the patent literature. For example:
U.S. Pat. No. 1,411,731 and U.S. Pat. No. 1,422,506 discloses diphenylguanidine as a rubber accelerator; PA1 U.S. Pat. No. 1,597,233 discloses N-o-tolyl-N'-phenyl-guanidine as a rubber accelerator; PA1 U.S. Pat. No. 1,672,431 discloses N,N'-di-o-methoxyphenyl-guanidine as being useful for therapeutic purposes, especially in the form of water-soluble salts; PA1 U.S. Pat. No. 1,730,338 discloses N-p-dimethyl-amino-phenyl-N'-phenylguanidine as a rubber accelerator; PA1 U.S. Pat. No. 1,795,738 discloses a process for the production of N,N'-dialkyl-di-substituted guanidines, including N-di-ethyl-N'-phenyl-guanidine, N-diethyl-N-isoamylguanidine, N-dimethyl-N'-isoamylguanidine and N-dimethyl-N'-ethylguanidine; PA1 U.S. Pat. No. 1,850,682 discloses a process for the preparation of disubstituted guanidine rubber accelerators bearing an additional substituent on the imine nitrogen atom; PA1 U.S. Pat. No. 2,145,214 discloses the use of disubstituted guanidines, e.g., diarylguanidines especially dixylylguanidine, as parasiticides; PA1 U.S. Pat. No. 2,254,009 discloses sym-di-2-octyl-guanidine and U.S. Pat. No. 2,274,476 and U.S. Pat. No. 2,289,542 disclose symdicyclohexylguanidine as insecticides and moth larvae repellents; PA1 U.S. Pat. No. 2,633,474 discloses 1,3-bis(o-ethylphenyl)guanidine and 1,3-bis(p-ethylphenyl)guanidine as rubber accelerators; PA1 U.S. Pat. No. 3,117,994 discloses N,N',N"-trisubstituted guanidines and their salts as bacteriostatic compounds; PA1 U.S. Pat. No. 3,140,231 discloses N-methyl- and N-ethyl-N'-octylguanidines and their salts as antihypertensive agents; PA1 U.S. Pat. No. 3,248,246 describes (Example 5) a 1,3-disubstituted guanidine whose substituents are hydrophobic hydrocarbon groups, one of which is naphthylmethyl and the other is n-butyl; PA1 U.S. Pat. No. 3,252,816 discloses various N-substituted and unsubstituted cinnamyl-guanidines and generically the corresponding N'- and N"-alkyl substituted compounds and their salts as antihypertensive agents; PA1 U.S. Pat. No. 3,270,054 discloses N-2-adamant-1-yl- and N-2-homoadamant-1-yl-oxy-ethyl-thioethyl- and aminoethyl-guanidine derivatives bearing at most two lower alkyl groups on the N'- and/or N"-nitrogen atom as sympathicolytic and anti-viral agents; PA1 U.S. Pat. No. 3,301,755 discloses N-ethylenically unsubstituted-alkyl-guanidines and the corresponding N'- and/or N"-lower alkyl compounds as hypoglycemic and antihypertensive agents; PA1 U.S. Pat. No. 3,409,669 discloses N-cyclohexylamino-(3,3-dialkyl-substituted-propyl)-guanidines and the corresponding N'-alkyl- and/or N"-alkyl-substituted compounds as hypotensive agents; PA1 U.S. Pat. No. 3,547,951 discloses 1,3-dioxolan-4-yl-alkyl-substituted guanidines which have anti-hypertensive activity and discloses lower alkyl, including n-butyl, as a possible substituent on the other amino group; PA1 U.S. Pat. No. 3,639,477 discloses propoxylguanidine compounds as having anorectic properties; PA1 U.S. Pat. Nos. 3,681,459; 3,769,427; 3,803,324; 3,908,013; 3,976,787; and 4,014,934 disclose aromatic substituted guanidine derivatives wherein the phenyl ring can contain hydroxy and/or halogen substituents for use in vasoconstrictive therapy; PA1 U.S. Pat. No. 3,804,898 discloses N-benzylcyclobutenyl and N-benzylcyclobutenyl-alkyl-guanidines and the corresponding N-alkyl and/or N"-alkyl-substituted compounds as hypotensive agents; PA1 U.S. Pat. No. 3,968,243 discloses N-aralkyl substituted guanidines and the corresponding N'-alkyl-N"-alkyl and N',N'-aralkyl compounds as being useful in the treatment of cardiac arrhythmias; PA1 U.S. Pat. No. 3,795,533 discloses o-halo-benzylidene-amino-guanidines and their use as anti-depressants for overcoming psychic depression; PA1 U.S. Pat. No. 4,007,181 discloses various N,N'-disubstituted guanidines substituted on the imine nitrogen atom by a adamantyl as possessing antiarrhythmic and diuretic activities; PA1 U.S. Pat. No. 4,051,256 discloses N-phenyl- and N-pyridyl-N'-adamantyl and cycloalkyl-guanidines as antiviral agents; PA1 U.S. Pat. No. 4,109,014 discloses N-hydroxysubstituted guanidines and the corresponding N-methyl disubstituted guanidines as vasoconstrictor agents; PA1 U.S. Pat. No. 4,169,154 discloses the use of guanidines in the treatment of depression; PA1 U.S. Pat. No. 4,393,007 discloses N-substituted and unsubstituted, N-substituted methyl-N'-unsubstituted, monosubstituted and disubstituted-N"-unsubstituted and substituted guanidines as ganglionic blocking agents; and PA1 U.S. Pat. No. 4,471,137 discloses N,N,N'N"-tetraalkyl guanidines as being sterically hindered bases useful in chemical synthesis. PA1 U.S. Pat. No. 4,709,094 discloses 1,3-disubstituted-guanidines, e.g., 1-3-dibutyl-guanidine and 1,3 di-o-tolyl-guanidine (DTG), as sigma brain receptor ligands. PA1 R.sub.1 and R.sub.2 are halogen, hydroxy, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy; PA1 R.sub.3, R.sub.3 ' and R.sub.3 " are hydrogen or C.sub.1 -C.sub.4 alkyl; PA1 R.sub.4 is hydrogen, C.sub.1 -C.sub.4 alkyl, hydroxy, C.sub.1-C.sub.4 alkoxy or an amino group; PA1 R.sub.5 and R.sub.6 are hydrogen, C.sub.1 -C.sub.6 alkyl, or an acyl group, or form a cyclic ring. Particular compounds disclosed in this patent document include 1-(2,6-dichlorophenyl)-2-(2,6-dichlorobenzylidine) aminoguanidine.multidot.HCl and 1-(2,6-dichlorophenyl)-2-cyclohexylidene-aminoguanidine. These compounds reportedly have antihypertensive properties. PA1 R.sup.1 is hydrogen, methyl or iso-butyl; PA1 NRR.sub.1 is morpholino; PA1 R.sub.2 and R.sub.3 are hydrogen, CHC.sub.6 H.sub.3 Cl.sub.2 (2,4-), isopropyl, C.sub.6 H.sub.4 p-Cl, CH(CH.sub.2).sub.10 CH.sub.3 or 1-(4-pyridyl)ethylidene. PA1 (a) contacting immobilized synaptosomes containing radiolabelled neurotransmitter with a compound suspected of inhibiting neurotransmitter release; PA1 (b) inducing, by depolarization, the release of radiolabelled neurotransmitter from the immobilized radiolabelled synaptosomes obtained in step (a); PA1 (c) washing the immobilized radiolabelled synaptosomes obtained in step (b) with a buffer comprising said compound and fractionating the effluent every 15 to 500 msec; and PA1 (d) detecting the relative amount of radiolabelled neurotransmitter in each fraction compared to control synaptosomes which have not been exposed to the compound of interest;
For examples of other substituted guanidines, see, e.g., U.S. Pat. Nos. 1,422,506; 1,642,180; 1,756,315; 3,159,676; 3,228,975; 3,248,426; 3,283,003; 3,320,229; 3,479,437; 3,547,951; 3,639,477; 3,784,643; 3,949,089; 3,975,533; 4,060,640 and 4,161,541.
Geluk, H. W., et al., J. Med. Chem. 12: 712 (1969) describe the synthesis of a variety of adamantyl disubstituted guanidines as possible antiviral agents, including N,N'-di-(adamantan-1-yl)-guanidine hydrochloride, N-(adamantan-1-yl)-N'-cyclohexyl-guanidine hydrochloride and N-(adamantan-1-yl)-N'-benzyl-guanidine hydrochloride.
PCT Application Publication No. WO88/00583 discloses diadamantylguanidine and N,N'-di-(2-adamantyl)guanidine. These compounds are reportedly useful for treating schizophrenia, psychosis, and depression.
Vasilev, P., et al., Chem. Abstr. 93: 150095u, discloses a compound with the following formula: ##STR1##
This compound reportedly has virucidal activity.
Ginsburg, V. A., et al., Chem. Abstr. 4518d (1962), and Ginsburg, V. A., et al., Zhurnal Organ. Khimii 7: 2267-2270 (1971), disclose a compound having the formula: ##STR2##
Kreutzberger and Schuker, Arch Pharmz. Ber. Deut. Pharm. Ges. 305: 400-405 (1975), disclose a compound having the formula: ##STR3##
German Patent No. DE 2,452,691, discloses a compound having the formula: ##STR4## wherein, inter alia, R.sub.0 is hydrogen, halogen, hydroxy, alkoxy or C.sub.1 -C.sub.6 alkyl;
Sunderdick, R., et al., Chem. Abstr. 81: 91439m (1974), disclose a compound having the formula: ##STR5## wherein R.dbd.Ph or cyclohexyl.
Bent, K. J., et al., Chem. Abstr. 74: 63479m (1971), is an abstract of German Patent No. 2,029,707. This patent discloses antiviral compounds having the formula: ##STR6## wherein: R is amino, methyl, iso-butyl or p-substituted phenyls;
Huisgen et al., Chem. Abstr. 63: 2975d (1965), disclose a compound having the formula: ##STR7##
Kroeger, F., et al., Chem. Abstr. 60: 9264f, disclose a compounds having the formulae: ##STR8##
Heinisch, L., J. Pract. Chem. 329: 290-300 (1987), discloses a compound having the formula: ##STR9##
Kramer, C. -R., et al., Biochem. Physiol. Pflanzen. 178: 469-477 (1983), disclose a compound having the formula: ##STR10## wherein R is hydrogen, methyl, butyl, hexyl, benzyl and phenyl, and R' is hydrogen or methyl. These compounds reportedly have algicidic activity.
Prasad, R. N., et al., Can. J. Chem. 45: 2247-2252 (1967), disclose a compound having the formula: ##STR11## wherein R and R' are hydrogen or Cl.sub.2 --CH--CO--, R.sub.2 is hydrogen, and R' is any one of a number of substituents having the general formula alkyl.dbd.N--. These compounds were evaluated for their antibacterial activity.
Huisgen et al., Chem. Ber. 98: 1476-1486 (1965), disclose a compound having the formula: ##STR12##
Podrebarac, E. G., et al., J. Med. Chem.: 283-288 (1963), disclose compounds having the formula: ##STR13## wherein the R groups may be hydrogen or methyl. These compounds were intermediates for the preparation of methylglyoxal bis(guanylhydrazone) analogs which may have activity against adult acute myelocytic leukemia.
Kroger et al., Ber. 97: 396-404 (1964), disclose a compound having the formula: ##STR14##
Durant, G. J., et al., J. Med. Chem.: 22-27 (1966), disclose a compound having the formula: ##STR15## wherein R is an alkyl, halo, or alkoxy group. These compounds reportedly have antiinflammatory activity.
The amino acid L-glutamate is widely thought to act as a chemical transmitter substance at excitatory synapses within the central nervous system. Neuronal responses to glutamate are complex and appear to be mediated by at least three different receptor types, i.e., KA, QA and NMDA subtypes, each being named for their relatively specific ligands, i.e., kainic acid, quisaqualic acid and N-methyl-D-aspartic acid, respectively. An amino acid which activates one or more of these receptor types is referred to as an excitatory amino acid (EAA).
The NMDA subtype of excitatory amino acid receptors is activated during normal excitatory synaptic transmission in the brain. Activation of NMDA receptors under normal conditions is responsible for the phenomena of long-term potentiation, a memory-like phenomenon, at excitatory synapses. Excessive excitation of neurons occurs in epileptic seizures and it has been shown that over-activation of NMDA receptors contributes to the pathophysiology of epilepsy.
NMDA receptors are also strongly involved in nerve cell death which occurs following brain or spinal chord ischemia. Upon the occurrence of ischemic brain insults such as stroke, heart attack or traumatic brain injury, an excessive release of endogenous glutamate occurs, resulting in the over-stimulation of NMDA receptors. Associated with the NMDA receptor is an ion channel. The recognition site, i.e., the NMDA receptor, is external to the ion channel. When glutamate interacts with the NMDA receptor, it causes the ion channel to open, thereby permitting a flow of cations across the cell membrane, e.g., Ca.sup.2+ and Na.sup.+ into the cell and K.sup.+ out of the cell. It is believed that this flux of ions, especially the influx of Ca.sup.2+ ions, caused by the interaction of glutamate with the NMDA receptor, plays an important role in nerve cell death. See, e.g., Rothman, S. M. and Olney, J. W., Trends in Neurosci. 10(7): 299-302 (1987).
In vitro studies have clearly demonstrated that activation of KA receptors can cause excitatory neuronal damage, although longer exposures are required (Koh, J. Y. et al., J. Neurosci. 10: 693-705 (1990); and Frandsen, A. J. et al., J. Neurochem. 33: 297-299 (1989)). The competitive KA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo-quinozaline (NBQX) is effective in preventing delayed neuronal degeneration following transient forebrain ischemia in rodents (Sheardown, M. J. et al., Science 247: 571-574 (1990). However, such effects require relatively large and potentially toxic systemic doses of NBQX, apparently because this compound exhibits poor penetration of the blood-brain barrier.
At present, there is a critical need for effective treatments which limit the extent of nerve cell death following a stroke or traumatic brain injury. Recent advances in the understanding of the mechanisms underlying this nerve cell death have led to the hope that a drug treatment can be developed. Research and development efforts in this area have focussed on blocking the actions of glutamate that are mediated by the NMDA receptor-channel complex. Two approaches are well developed: competitive NMDA receptor antagonists (Choi D. W. (1990) Cerebrov. Brain Metab. Rev. 1: 165-211; Watkins, J. C. and Olverman, H. J. (1987) Trends Neurosci. 10: 265-272) and blockers of the ion channel of the NMDA receptor-channel complex (Meldrum, B. (1990) Cerebrovascular Brain Metab. Rev. 2: 27-57; Choi, D. W. (1990) Cerebrovascular Brain Metab. Rev. 2: 105-147; and Kemp, J. A. et al., Trends Neurosci. 10: 265-272 (1987)). The ion-channel blocker MK-801 is an effective neuroprotective agent in a variety of in vivo models of stroke (Meldrum, B. (1990) Cerebrovascular Brain Metab. Rev. 2: 27-57; Albers, G. W. et al., Annals Neurol. 25: 398-403 (1989)). However, there is some toxicity associated with this class of compounds (Olney, J. W. et al., Science 244: 1360-1362 (1989); Koek, W. and Colpaert, J. (1990) J. Pharmaco. Exp. Ther. 252: 349-357) and NMDA antagonists have been shown to inhibit memory acquisition (Morris, R. G. M. (1988) in Excitat. A. A.'s in Health and Disease, D. Lodge (ed.), Wiley, 297-320). These side effects may limit the clinical use of such agents to acute situations.
Blockers of neurotransmitter release have also received some attention as potential neuroprotective agents. For example, adenosine analogs may indirectly attenuate neurotransmitter release via G-protein-mediated inhibition of presynaptic Ca channels (Meldrum, B. Cerebrovascular and Brain Metab. Rev. 2: 27-57 (1990); Dolphin, A. C. Nature 316: 148-150 (1985)). It has been shown that such compounds are neuroprotective during ischemia in various rodent models of stroke (Evans , M. C. et al. Neurosci. Lett. 83: 287-292 (1987)). Ault, B. and Wang, C. M., Br. J. Pharmacol. 87: 695-703 (1986), disclose that adenosine inhibits epileptiform activity in hippocampal slices.
Other putative blockers of glutamate release act by an as yet undefined mechanism. The substituted piperidine derivative 2-(4-(p-fluorobenzoyl)piperidin-1-yl)-2'-acetonaphthone (E-2001) (Kaneko, T. et al. Arzneim-Forsch./Drug Res. 39: 445-450 (1989)) and the compound PK 26124 (riluzole, 2-amino-6-trifluoromethoxybenzothiazole) (Malgouris, C. et al. J. Neurosci 9: 3720-3727 (1989)) have been shown to be neuroprotective in rodents. PK 26124, at therapeutic dosages in rats, does not seem to produce MK-801-like behavioral side effects in a controlled comparison of its efficacy/safety ratio with that of MK-801 (Koek, J. W. and Colpaert, F. C., J. Pharmacol. Exp. Ther. 252: 349-357 (1990)). E-2001 ameliorates the degeneration of pyramidal neurons in the hippocampal CA1 sector following transient ischemia in Mongolian gerbils. In addition, E-2001 improves stroke symptoms induced by permanent unilateral carotid artery ligation in gerbils, prolonged the survival time following permanent bilateral carotid artery ligation in gerbils and mice, and prolonged the survival time following intravenous injection of KCN into mice. Kaneko, T. et al., Arzneim.-Forsch./Drug Res. 39: 445-450 (1989).
It is believed that glutamate neurotoxicity is involved in acute injury to the nervous system as observed with seizure, hypoxia, hypoglycemia, and trauma, as well as in chronic degenerative diseases such as Huntington's disease, olivopontocereballar atrophy associated with glutamate dehydrogenase deficiency and decreased glutamate catabolism, Guam amyotrophic lateral sclerosis/Parkinsonium-dementia, Parkinson's disease, and Alzheimer's disease. Choi, D. W., Neuron 1: 623-634 (1988); Choi, D. W., Cereb. Brain Met. Rev. 2: 105-147 (1990).
Langlais, P. L. et al., J. Neurosci 10: 1664-1674 (1990), disclose that glutamate and GABA may be involved in pyrithiamine-induced thiamine deficiency (PTD) which causes the formation of thalamic lesions and seizures. Administration of the NMDA receptor antagonist MK-801 during the late stages of PTD resulted in a marked attenuation of necrotic damage to the thalamus and periacqueductal gray and a reduction in the number and size of hemorrhagic lesions. Since thiamine deficiency is responsible for similar damage in Wernicke-Korsakoff's syndrome, Langlais et al. suggest that these results provide an important rational for the treatment of this human neuropathic condition.
Malgouris, C. et al., J. Neurosci. 9: 3720-3727 (1989), disclose that PK 26124 (riluzole), a compound which inhibits glutamate release from nerve terminals, has anticonvulsant activity, improves sleep quality in rodents, and is active in protecting the rodent brain from the cellular and functional consequences of ischemia, including the prevention of memory loss and hippocampal neuronal damage.
Miller, et al., New Anticonvulsant Drugs, Meldrum, B. S. and Porter R. J. (eds), London: John Libbey, 165-177 (1986), disclose that the glutamate release blocker lamotragine is an anticonvulsant.
Price, M. T. and Olney, J. W., Soc. Neurosci. Abstr. 16: 377, abstr. 161.16 (1990), disclose that the administration of EAA antagonists completely prevented emesis in ferrets that were subject to chemotherapy with cisplatin. The EAA antagonists employed did not penetrate the blood-brain barrier, and it was thus suggested that such compounds way prevent nausea, a common side effect during cancer chemotherapy.
Calcium antagonists such as nimodipine act both as cerebral vasodilators (Wong, M. C. W. and Haley, E. C. Jr., Stroke 24: 31-36 (1989)), and to block calcium entry into neurons (Scriabine , A. Adv. Neurosurg. (1990)). Modest improvement in the outcome of stroke has been observed in clinical trials (Gelmers, H. J. et al., N. Eng. J. Med. 318: 203-207 (1988)). While there are significant cardiovascular side effects, nimodipine appears less toxic than the NMDA antagonists and may find a role in the chronic treatment of stroke and other neurological disorders.
There are at least 3 subclasses of Ca channels, "T", "N", and "L", that differ in their pharmacology, location in neuronal and non-neuronal tissues, and physiological properties (Nowycky, M. C. et al. Nature 316: 440-443 (1985); Bean, B. P. Ann. Rev. Physiol. 51: 367-384 (1989)). Voltage-sensitive calcium channels (VSCC) in presynaptic nerve terminals control the influx of Ca.sup.2+ and thereby determine the quantity and duration of transmitter released by the presynaptic action potentials. Biochemical .sup.45 Ca tracer flux experiments with isolated nerve endings (synaptosomes) indicate that K.sup.+ -depolarization dependent .sup.45 Ca entry consists of fast transient and slow sustained components. The transient Ca influx has been determined to represent a channel mediated process, whereas the sustained component reflects Ca entry via reversed Na/Ca exchange (Turner, T. and Goldin, S., J. Neurosci. 5: 841-849 (1985); Suskziw, J. B. NATO ASI Series, H21: 286-291 (1988); Suszkiw, J. B. et al. J. Neurochem. 42: 1260-1269 (1989)).
European Patent Application No. 0 266 574, discloses that calcium overload blockers will be useful in the treatment of anoxia, ischemia, migraine and epilepsy. This application also discloses that certain piperidine derivatives have activity against calcium overload in the brain and may be used in the treatment of migraine.
Dreyer, E. B. et al., Science 248: 364-367 (1990), disclose that the HIV-1 coat protein gp120 produces neuronal cell injury which may be responsible for the dementia and blindness encountered in acquired immunodeficiency syndrome (AIDS). Calcium channel antagonists prevented the gp120-induced neuronal injury of retinal ganglion cells. Dreyer et al. propose that calcium channel antagonists may prove useful in mitigating HIV-1 related neuronal injury.